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Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability [bulk RNA-seq]

ABSTRACT: In this study, we performed network analysis on Hi-C data and identified a group of non-coding regions forming many 3D contacts (referred to as hubs). Through a high-throughput CRISPR-Cas9 library screening by targeted deletion, we discovered that some hubs without any epigenetic marks were essential for cell growth and survival. Hi-C and single cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and impact the distal genes expression. This study revealed the 3D structural importance of non-coding loci that are not associated with any functional element, providing a new mechanistic understanding of disease-associated genetic variations. Furthermore, our analyses also suggest a powerful approach to develop "one-drug-multiple-targets" therapeutics targeting disease-specific non-coding regions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176501 | GEO | 2021/08/25

REPOSITORIES: GEO

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Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability [HiC]

Project description:Most non-coding regions of the human genome do not harbour any annotated element and are even not marked with any epigenomic or protein binding signal. However, an overlooked aspect of their possible role in stabilizing 3D chromatin organization has not been extensively studied. To illuminate their structural importance, we started with the non-coding regions forming many 3D contacts (referred to as hubs) and performed a CRISPR library screening to identify dozens of hubs essential for cell viability. Hi-C and single cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and impact the distal genes expression. This study revealed the 3D structural importance of non-coding loci that are not associated with any functional element, providing a new mechanistic understanding of disease-associated genetic variations (GVs), and we focused on single nucleotide variations. Furthermore, our analyses also suggest a powerful approach to develop "one-drug-multiple-targets" therapeutics targeting disease-specific non-coding regions.

2021-08-25 | GSE176500 | GEO

Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability [single-cell RNA-seq]

2021-08-25 | GSE176502 | GEO

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [RNA-seq]

Project description:Mammalian sex is determined by a network of antagonistic genes that are well characterized. However, its non-coding regulation is still largely unknown. Here we explore the 3D chromatin landscape of sex determination in vivo. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis approach that identifies 3D regulatory hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, which deletion results in male-to-female sex reversal.

2022-11-21 | GSE217617 | GEO

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [Hi-C]

2022-11-21 | GSE217616 | GEO

Unbiased Capture Hi-C reveals the potential targets of breast cancer susceptibility loci

Project description:Genome-wide association studies have identified over 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions; several map to gene deserts, regions of several hundred kb lacking protein-coding genes. We hypothesized that gene deserts harbour long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21 and 9q31.2. We identified interaction peaks between putative regulatory elements ("bait fragments") within the captured regions and "targets" that included both protein-coding genes and long non-coding (lnc)RNAs, over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2 and MYC; target lncRNAs included DIRC3, PVT1 and CCDC26. For two gene deserts we were able to define a set of SNPs that were correlated with the published risk variant and that clustered within the bait end of an interaction peak. Preliminary functional analyses implicate one SNP (rs12613955; 2q35) as a potentially functional variant. Capture Hi-C was carried out in BT483, SUM44, and GM06990 cell lines to investigate breast cancer risk loci 2q35, 8q24.21 and 9q31.2.

2014-08-04 | E-GEOD-55634 | biostudies-arrayexpress

Unbiased Capture Hi-C reveals the potential targets of breast cancer susceptibility loci

2014-08-04 | GSE55634 | GEO

Whole genome shotgun bisulfite sequencing of the Lsh-/- and Lsh+/+ murine embryonic fibroblasts and ES cells

Project description:Whole-genome single-base resolution methylcytosine map reveals profound changes that occur after Lsh deletion during embryonic development in primary WT and Lsh-/- MEFs. Lsh deletion leads to widespread decreases of CG methylation level at uniquely mapped genomic regions compared to wild type, including TSSs at protein-coding genes, and non-coding RNA genes. MethylC-Seq from Mus musculus primary MEFs.

2014-06-13 | E-GEOD-57486 | biostudies-arrayexpress

Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin hubs

Project description:We have analyzed publicly available K562 Hi-C data, which enables genome-wide unbiased capturing of chromatin interactions, using a Mixture Poisson Regression Model to define a highly specific set of interacting genomic regions. We integrated multiple ENCODE Consortium resources with the Hi-C data, using DNase-seq data and ChIP-seq data for 46 transcription factors and 8 histone modifications. We classified 12 different sets (clusters) of interacting loci that can be distinguished by their chromatin modifications and which can be categorized into three types of chromatin hubs. The different clusters of loci display very different relationships with transcription factor binding sites. As expected, many of the transcription factors show binding patterns specific to clusters composed of interacting loci that encompass promoters or enhancers. However, cluster 6, which is distinguished by marks of open chromatin but not by marks of active enhancers or promoters, was not bound by most transcription factors but was highly enriched for 3 transcription factors (GATA1, GATA2, and c-Jun) and 3 chromatin modifiers (BRG1, INI1, and SIRT6). To validate the identification of the clusters and to dissect the impact of chromatin organization on gene regulation, we performed RNA-seq analyses before and after knockdown of GATA1 or GATA2. We found that knockdown of the GATA factors greatly alters the expression of genes within cluster 6. Our work, in combination with previous studies linking regulation by GATA factors with c-Jun and BRG1, provide genome-wide evidence that Hi-C data identifies sets of biologically relevant interacting loci. RNA-seq of control, siGATA1 and siGATA2 K562 cells

2012-06-30 | E-GEOD-32213 | biostudies-arrayexpress

Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of lincRNA genes in human cells

Project description:Characterizing the relationship between genome form and function requires methods both for zooming out, to globally survey the genomic architectural landscape, and for zooming in, to investigate regions of interest at high resolution. High throughput methods based on chromosome conformation capture (3C) have greatly advanced our understanding of the three-dimensional (3D) organization of genomes, but are limited in resolution by their reliance on restriction enzymes. Here we describe a method for comprehensively mapping global chromatin contacts that uses DNaseI for chromatin fragmentation, leading to greatly improved efficiency and resolution. Coupling this method with DNA capture technology provides a high-throughput approach for targeted mapping of fine-scale chromatin architecture. We applied targeted DNase Hi-C to characterize the 3D organization of 1,030 lincRNA promoters in two human cell lines, and identified thousands of high-confidence lincRNA promoter-associated chromatin contacts at 1 kilobase pair (kbp) resolution. Detailed analysis of these contacts reveals that expression of lincRNAs is tightly controlled by complex mechanisms involving both super-enhancers and the polycomb repressive complex. Our results provide the first glimpse of the cell-type-specific 3D organization of lincRNA genes. DNase Hi-C assay (x1 replicate) in H1 and K562 cells, respectively. Targeted DNase Hi-C assays of the 220kb promoter-enhancer library (x1 replicate) and the 5Mb lincRNA promoter library (x2 replicate), in H1 and K562 cells, respectively.

2014-11-01 | E-GEOD-56869 | biostudies-arrayexpress

Cytoplasmic cleavage of IMPA1 3’UTR is necessary for maintaining axon integrity.

Project description:The 3’ untranslated regions (3’UTRs) of messenger RNAs (mRNA) are non-coding sequences involved in many aspects of mRNA metabolism, including intracellular localisation and translation. Incorrect processing and delivery of mRNA causes severe developmental defects and has been implicated in many neurological disorders. Here, we use deep sequencing to show that in sympathetic neuron axons, the 3’UTRs of many transcripts undergo cleavage, generating isoforms that express the coding sequence with a short 3’UTR, and stable 3’UTR-derived fragments of unknown function. Cleavage of the long 3’UTR of Inositol Monophosphatase 1 ( IMPA1 ), mediated by a protein complex containing the endonuclease Ago2 and the RNA binding protein HuD, generates a translatable isoform that is necessary for maintaining the integrity of sympathetic neuron axons. Thus, our study provides a new mechanism of mRNA metabolism that simultaneously regulates local protein synthesis and generates a yet undescribed class of non-coding RNAs.

2020-12-31 | GSE160025 | GEO

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